Mice lacking the signaling molecule CaIDAG-GEFI represent a model for leukocyte adhesion deficiency type III

Single gene mutations in beta integrins can account for functional defects of individual cells of the hematopoietic system. In humans, mutations in beta(2) integrin lead to leukocyte adhesion deficiency (LAD) syndrome and mutations in beta(3) integrin cause the bleeding disorder Glanzmarm thrombasthenia. However, multiple defects in blood cells involving various beta integrins (beta(1), beta(2), and beta(3)) occur simultaneously in patients with the recently described LAD type III (LAD-III). Here we show that the product of a single gene, Ca2+ and diacylglycerol-regulated guanine nucleotide exchange factor 1 (CaIDAG-GEFI), controlled the activation of all 3 integrins in the hematopoietic system. Neutrophils from CalDAG-GEFI(-/-) mice exhibited strong defects in Rap1 and beta(1) and beta(2) integrin activation while maintaining normal calcium flux, degranulation, and ROS generation. Neutrophils from CalDAG-GEFI deficient mice failed to adhere firmly to stimulated venules and to migrate into sites of inflammation. Furthermore, CaIDAG-GEFI regulated the activation of beta(1) and beta(3) integrins in platelets, and CaIDAG-GEFI deficiency caused complete inhibition of arterial thrombus formation in mice. Thus, mice engineered to lack